Long non-coding RNA LINC01133 silencing exerts antioncogenic effect in pancreatic cancer through the methylation of DKK1 promoter and the activation of Wnt signaling pathway

Abstract

ABSTRACT Recent studies have acknowledged the critical roles played by long non-coding RNAs (lncRNAs) in the development and progression of pancreatic cancer. Therefore, the present study aimed to elucidate the mechanism underlying on how LINC01133 regulates the Wnt signaling pathway in pancreatic cancer. A microarray-based gene expression analysis was performed to identify the differentially expressed lncRNAs in pancreatic cancer. In addition, ectopic expression assays, knockdown experiments and gene reporter assays were conducted to clarify the role of LINC01133 in pancreatic cancer and to understand the interaction between LINC01133 and the methylation of DKK1 promoter. The expression of LINC01133, DKK1, and other genes related to the Wnt signaling pathway was also measured. EDU staining, scratch test and Transwell assay were employed to measure the proliferation, migration and invasion of pancreatic cancer cells, respectively. GSE32676 and GSE16515 revealed that LINC01133 was upregulated in pancreatic cancer, which was also associated with increased DKK1 methylation and higher expression of genes related to the Wnt signaling pathway, although the expression of DKK1 decreased in pancreatic cancer. In addition, LINC01133 bound to the promoter region of DKK1, resulting in the trimethylation of H3K27 and decreased DKK1 expression, while the expression of Wnt-5a, MMP-7, and β-catenin increased upon LINC01133 binding. Finally, over-expressed LINC01133 enhanced the growth, proliferation, migration, metastasis, and invasion of pancreatic cancer cells. The present study clarified the distinct effect of LINC01133 on pancreatic cancer. In summary, by inducing the methylation of DKK1 promoter, LINC01133 silencing suppresses the development of pancreatic cancer cells through the Wnt signaling pathway.